Fast melt multiparticulate formulations for oral delivery

ABSTRACT

A drug formulation for gastrointestinal deposition, said formulation comprising a free flowing plurality of particles comprising an active agent and a water-soluble excipient, wherein the particles have a mean diameter of greater than about 10 ┘m to about 1 mm, and the formulation is capable of dissolving or dispersing in a patient&#39;s mouth within 1 minute after administration without the co-administration of a fluid.

[0001] This application claims priority from U.S. ProvisionalApplication No. 60/362,307 filed on Mar. 7, 2002 and No. 60/366,710filed Mar. 22, 2002, the entire disclosures of which are herebyincorporated by reference.

DESCRIPTION

[0002] The present is directed to fast melt multiparticulateformulations for oral use. The multiparticulates can be used in amultiple dose delivery device which dispenses a unit dose of the powderupon actuation, or can be packaged for dispensation in sachets or likeunit dose containers.

[0003] The most prominent mode of delivery of therapeutic agents is bythe oral route by means of solid dosage forms such as tablets andcapsules. Oral administration of solid dosage forms is more convenientand accepted than other modes of administration, e.g., parenteraladministration. However, the manufacture, dispensing and administrationof solid dosage forms are not without associated problems and drawbacks.

[0004] With the manufacture of solid dosage forms, in addition to theactive agent, it is necessary to combine other ingredients in theformulations for various reasons, such as to enhance physicalappearance, to provide necessary bulk for tableting or capsuling, toimprove stability, to improve compressibility or to aid indisintegration after administration. However, these added excipientshave been shown to adversely influence the release, stability andbioavailability of the active ingredient. The added excipients are aparticular problem with drugs which require a high dose in order toprovide a therapeutic effect, e.g., biphosphonate drugs. The inclusionof the additional excipient can make the final tablet extremely largewhich could result in esophogeal damage due to the physicalcharacteristics of the dosage form if it is not swallowed properly.Esophogeal damage can also be caused by toxicity caused by the drugitself, if the tablet becomes lodged in the throat or has an increasedtransit time through the esophagus, due to its increased size.

[0005] Further, the tableting of certain drugs has many associatedproduction problems. In particular, many drugs, e.g., paracetamol(acetaminophen), have poor compressibility and cannot be directlycompressed into solid dosage forms. Consequently, such drugs must eitherbe wet granulated or manufactured in a special grade in order to betableted which increases manufacturing steps and production costs.

[0006] The adherence to good manufacturing practices and processcontrols is essential in order to minimize dosage form to dosage formand batch to batch variations of the final product. Even strictadherence to these practices still is not a guarantee that acceptablevariation will occur.

[0007] With the high cost of industrial scale production andgovernmental approval of solid dosage forms, such formulations are oftenavailable in a limited number of strengths, which only meet the needs ofthe largest sectors of the population. Unfortunately, this practiceleaves many patients without acceptable means of treatment andphysicians in a quandary with respect to individualizing dosages to meetthe clinical needs of their patients.

[0008] The dispensing of oral solid dosage forms also makes theformulations susceptible to degradation and contamination due torepackaging, improper storage and manual handling.

[0009] There are also many patients who are unable or unwilling to takeconventional orally administered dosage forms. For some patients, theperception of unacceptable taste or mouth feel of a dose of medicineleads to a gag reflex action that makes swallowing difficult orimpossible. Other patients, e.g., pediatric and geriatric patients, findit difficult to ingest typical solid oral dosage forms, e.g., due totablet size.

[0010] Other patients, particularly elderly patients, have conditionssuch as achlorhydria which hinders the successful use of oral soliddosage forms. Achlorhydria is a condition wherein there is an abnormaldeficiency or absence of free hydrochloric acid in the gastricsecretions of the stomach. This condition hinders the disintegrationand/or dissolution of oral solid dosage forms, particularly dosage formswith high or insoluble excipient payloads. Thus, as the present dosageform is in fast melt multiparticulate form, it does not need to undergodisintegration and/or dissolution to the same extent as solid dosageforms

[0011] Flavoured solutions/suspensions of some therapeutic agents havebeen developed to facilitate the oral administration of oral agents topatients normally having difficulty ingesting conventional solid oraldosage forms. While liquid formulations are more easily administered tothe problem patient, liquid/suspension formulations are not withouttheir own significant problems and restrictions. The liquid dose amountis not as easily controlled compared with tablet and capsule forms andmany therapeutic agents are not sufficiently stable insolution/suspension form. Indeed, most suspension type formulations aretypically reconstituted by the pharmacist and then have a limited shelflife even under refrigerated conditions. Another problem with liquidformulations which is not as much a factor with tablets and capsules isthe taste of the active agent. The taste of some therapeutic agents isso unacceptable that liquid formulations are not a viable option.Further, solution/suspension type formulations are typically notacceptable where the active agent must be provided with a protectivecoating, e.g. a taste masking coating or an enteric coating to protectthe active agent from the strongly acidic conditions of the stomach.

[0012] Fast melt drug formulations have also been developed tofacilitate the oral administration of oral agents to patients normallyhaving difficulty ingesting conventional solid oral dosage forms. Fastmelt formulations are typically in the form of tablets or lozenges thatdissolve or disperse in a patient's mouth within a minute without theneed of water or chewing. Drug delivery formulations which exhibit fastmelt properties can improve patient compliance due to the ease ofswallowing as well as the absence of a need for the co-administration ofwater or another fluid. Further, fast melt systems can be formulated asto have a superior taste and improved accuracy of dosing as compared toliquid preparations.

[0013] Other formulations which have been contemplated in order tofacilitate the oral administration of oral agents and to avoid theassociated problems of solid dosage forms are multiparticulate dosageforms as disclosed in WO 01/64182, the contents of which are herebyincorporated by reference.

[0014] According to a first aspect of the present invention, there isprovided a drug formulation for gastrointestinal deposition, saidformulation comprising a free flowing plurality of particles comprisingan active agent and a water-soluble excipient, wherein the particleshave a mean diameter of greater than about 10 μm to about 1 mm, and theformulation is capable of dissolving or dispersing in a patient's mouthwithin 1 minute after administration without the co-administration of afluid.

[0015] Thus, the present invention, in its first aspect, provides aformulation which exhibits the benefits of fast melt formulations aswell as the benefits of multiparticulate formulations. It alsofacilitates the delivery of a wide range of therapeutic agents forgastrointestinal deposition and minimizes pulmonary deposition ofmaterials having undesirable or unknown pulmonary toxicology but whichare approved for oral delivery. In some embodiments, the formulation cancontain minimal excipient and be used in a multiple dose delivery devicewhich dispenses a unit dose of the formulation upon actuation. Suchdelivery devices are disclosed in WO 01/64182.

[0016] In a second aspect, the present invention provides a drugformulation for gastrointestinal deposition, said formulation comprisinga free flowing plurality of particles and including an active agent anda water-soluble excipient, wherein the particles have a mean diameter ofgreater than about 10 μm to about 1 mm, and the excipient has a negativeheat of solution.

[0017] A significant advantage of formulations in accordance with thesecond aspect of the invention is that, when administered via the oralcavity, the local cooling caused by the water-soluble excipientdissolving in saliva serves to mask the taste of the active agent in amanner which does not delay the release, or dissolution of the activeagent itself.

[0018] Preferably, formulations in accordance with the second aspect ofthe invention are capable of dissolving or dispersing in a patient'smouth within one minute after administration, without theco-administration of a fluid. Such preferred formulations, therefore,are also examples of the first aspect of the invention and will provideall of the aforementioned benefits associated with the first aspect ofthe invention.

[0019] Drug formulations in accordance with either the first or thesecond aspect of the invention are preferably arranged for direct,un-encapsulated administration to a patient's oral cavity. It is alsopreferred for the particles to be non-compressed.

[0020] In embodiments, the particles each include both active agent andwater-soluble excipient. The particles can comprise a core and acoating, with the coating including a quantity of the water-solubleexcipient.

[0021] Preferably, and in accordance with either aspect of theinvention, the particles are formed by melt-coating core particles witha coating material that includes (and may consist of) a quantity of theexcipient, at a temperature below that at which the active agent meltsor decomposes. Forming the particles in this manner is considered toprovide them with surface properties that render them easily wetted andcapable of rapidly absorbing water from their environment and, thus,able to facilitate the rapid dissolution or dispersion of theformulation, especially the active agent, when the formulation isexposed to an aqueous environment, such as in the oral cavity.

[0022] A quantity of the active agent can be included in the core orcore particles and/or in the coating or coating material. In somepreferred embodiments, the coating or coating material is substantiallyfree of active agent, whereas in others, the core is substantially freeof active agent.

[0023] In further embodiments of either aspect of the invention, thecoating or coating material comprises a water-soluble or hydrophilicbinder. Preferably, the binder melts or softens sufficiently tomelt-coat the core particles at a temperature below that at which theactive agent melts or decomposes. In further embodiments, thewater-soluble excipient melts or softens sufficiently to melt-coat thecore particles at a temperature below that at which the active agentmelts or decomposes. In further preferred arrangements, the binder meltsor softens sufficiently to melt-coat the core particles at a temperaturebelow that at which the water-soluble excipient melts or decomposes. Insome embodiments of the invention, the coating or coating materialsubstantially completely covers the surface of the core or coreparticles.

[0024] Thus, particles in accordance with the present invention cancomprise a core that consists substantially or entirely of active agentsurrounded by a coating that comprises water-soluble excipient eitheralone, or in combination with a water-soluble or hydrophilic binder.When the water-soluble excipient is employed alone in such particles, itis preferred for it to be capable of melting or softening sufficientlyto melt-coat the core particles at a temperature below that at which theactive agent melts or decomposes. Where a binder is employed, thewater-soluble excipient need not be capable of melting or softening at atemperature below the melting or decomposition temperature of the activeagent. However, when such a high melting point water-soluble excipientis employed, the binder should be capable both of melting or softeningsufficiently to melt-coat the core particles at a temperature below thatat which the active agent melts or decomposes, and of binding thewater-soluble excipient in the coating.

[0025] The core or core particles, in addition to including activeagent, can also include a quantity of the water-soluble excipient and/oran additional excipient, which may also be water soluble, but which doesnot necessarily qualify as a water-soluble excipient in accordance withthe present invention. For example, the core can comprise a granulationof such an additional excipient (e.g. polyvinyl alcohol, orpolyvinylpyrrolidine) and active agent, or consist of a particle (e.g. amicrocrystalline cellulose sphere) of additional excipient coated withactive agent.

[0026] In other embodiments in accordance with the invention, the corecan consist entirely of water-soluble excipient. In such embodiments,the coat or coating material comprises active agent and either anadditional quantity of water-soluble excipient, or a binder. When thecoat or coating material comprises active agent and binder, additionalwater-soluble excipient can also be present in therein.

[0027] It is preferred that formulations in accordance with eitheraspect of the present invention are formed by a process in which theactive agent is not raised to or above its melting point, or atemperature at which a significant proportion thereof is caused todecompose.

[0028] The melting point of the water-soluble excipient is preferablyequal to or below 150, 120 or 110° C., and is preferably at least 40 or50° C. Preferably, the excipient melts at around or below 100° C. Themelting point of the binder, if employed, is preferably equal to orbelow 150, 120 or 110° C., and is preferably at least 40 or 50° C.

[0029] More preferably, the binder melts at around or below 100° C. Incertain embodiments, the melting point of the excipient exceeds that ofthe binder.

[0030] The water-soluble excipient, preferably, has a heat of solutionequal to or below −7 KCal/Kg. More preferably, the heat of solution ofthe water-soluble excipient is equal to or below −10, −15, −20, −25, or−30 KCal/Kg. The solubility in water of the water-soluble excipient ispreferably at least 20, 30 or 40% w/w at 25° C.

[0031] The water-soluble excipient is preferably a sugar, sugar alcohol,polyethylene glycol (PEG), or polyethylene oxide, and is preferably notlactose. Formulations in accordance with the invention, preferably, arelactose free. The preferred water-soluble excipients are the sugaralcohols including, but not limited to sorbitol, mannitol, maltitol,reduced starch saccharide, xylitol, reduced paratinose, erythritol, andcombinations thereof. The preferred sugar is glucose. Other suitablewater-soluble excipients include gelatin, partially hydrolyzed gelatin,hydrolyzed dextran, dextrin, alginate and mixtures thereof.

[0032] Preferred binders include polyethylene glycols (PEG) andpolyethylene oxides.

[0033] In further preferred embodiments, the core or core particlesinclude an additional excipient for controlling or delaying the releaseof the active agent. In this regard, the core or core particles caninclude a layer or coating of such an additional excipient encapsulatingan inner core comprising the active agent. The additional excipient canbe selected from those known to persons skilled in the art to be capableof controlling the release of an encapsulated active agent. Suchexcipients include those commonly used to provide enteric and sustainedrelease coatings. Examples of the former include cellulose acetatephthalate, hydroxypropyl-methylcelluose phthalate, polymethacrylates,such as Eudragit® L 100-55 or L 30 D-55, and Shellac. Examples of thelatter include ethylcellulose, hydroxypropyl-celluose,hydroxypropylmethylcelluose, and polymethacrylates, such as Eudragit® RLand RS film-coating systems.

[0034] In alternative embodiments, formulations in accordance with theinvention can provide rapid release of the active agent. In this regard,the term “rapid release” should be understood to mean that suchformulations release at least 80% of their active agent within 45minutes in standard dissolution tests. In the case of poorly solubleactive agents, such formulations typically release at least 80% of theiractive agent within 40, 30, 20, 15 and preferably 10 minutes after beingadministered to a patient's oral cavity. In the case of more solubleactive agents, such formulations typically release at least 80% of theiractive agent within 10, 7 and preferably 5 minutes after beingadministered to a patient's oral cavity. In particularly preferredembodiments of the invention, the active agent will dissolve into anaqueous environment more rapidly from a formulation in accordance withthe invention than it would if it had not been incorporated in such aformulation.

[0035] In a third aspect, the present invention provides a method ofpreparing a drug formulation in accordance with the first or secondaspect of the invention, comprising forming the particles bymelt-coating core particles with a coating material that includes aquantity of the water-soluble excipient, at a temperature below themelting point or decomposition temperature of the active agent.

[0036] In a further aspect, the invention provides the use of a drugformulation in accordance with the first or second aspect of theinvention, or a drug formulation prepared by a method in accordance withthe third aspect of the invention, for the preparation of a medicamentfor treating a human or animal patient, wherein the formulation isadministered directly and in an un-encapsulated form to the patient'soral cavity. The invention also provides a method of treating a human oranimal patient, wherein a formulation in accordance with the first orsecond aspect of the invention, or prepared by a method in accordancewith a third aspect of the invention, is administered in aun-encapsulated form directly into the patient's oral cavity.

[0037] It is also possible for formulations in accordance with eitherthe first aspect or the second aspect of the invention to includeadditional particles with different properties to those described above.For example, the additional particles may not include any active agent.

[0038] Certain embodiments of the invention comprise a fast meltmultiparticulate formulation which contains a salivary stimulant tofacilitate hydration of the formulation and the swallowing of a unitdose of the multiparticulates upon oral delivery.

[0039] Certain embodiments of the invention comprise a fast meltmultiparticulate formulation which has a desired particle range in orderto minimize pulmonary aspiration of particles.

[0040] Fast melt multiparticulate formulations in accordance with theinvention are, preferably, divisable into unit doses (e.g. with the useof a multiple unit dosing device) with a weight uniformity which iswithin the acceptable range of weight uniformity for tablets orcapsules. A detailed discussion of weight uniformity can be found in theUSP/NF 23/18 section 905, which is hereby incorporated by reference inits entirety for all purposes.

[0041] The invention also provides methods of preparing fast meltmultiparticulate dosage forms and systems disclosed herein. Theinvention further provides methods of preparing fast meltmultiparticulate dosage forms without the use of an aqueous fluid as aprocessing aid.

[0042] The invention additionally provides methods of preparing multipleunit delivery systems containing fast melt multiparticulate dosage formsin accordance with the invention.

[0043] The invention also provides methods of preparing fast meltmultiparticulate dosage forms having a desired particle size range.

[0044] The invention further provides methods of administering an activeagent comprising administering a fast melt multiparticulate dosage form.

[0045] The invention additionally provides methods of administering anactive agent comprising administering a fast melt multiparticulatedosage form via the use of a multiple unit delivery system.

[0046] In certain embodiments, the present invention is directed to adrug formulation for gastrointestinal deposition comprising anon-compressed free flowing plurality of particles comprising an activeagent and a water-soluble excipient, the particles having a meandiameter of greater than 10 μm to about 1 mm, the particles comprisingat least about 50% drug and the formulation dissolving in a patient'smouth within 1 minute after administration without the co-administrationof a fluid.

[0047] In certain embodiments, the invention is directed to a method oftreating a patient with an active agent for gastrointestinal depositioncomprising administering a formulation comprising a non-compressed freeflowing plurality of particles comprising an active agent and awater-soluble excipient, the particles having a mean diameter of greaterthan 10 μm to about 1 mm, and the formulation dissolving in a patient'smouth within 1 minute after administration without the co-administrationof a fluid.

[0048] In certain embodiments, the invention is directed to a drugdelivery system for delivery of a drug for gastrointestinal deposition.The system comprises a multiple unit dosing device comprising a housingand an actuator, the device containing multiple doses of a fast meltmultiparticulate formulation, the device upon actuation delivering aunit dose of the fast melt multiparticulates for gastrointestinaldeposition, the multiparticulates having a mean particle size of greaterthan 10 μm and preferably less than about 1 mm in order to minimizepulmonary deposition of the multiparticulates and such that an effectivedose of the drug cannot be delivered into the lower lung of a humanpatient. The drug delivery system can be used to administer the unitdose of fast melt multiparticulates into the oral cavity of the patient(in-vivo) or to dispense the unit dose into an intermediate receptacle(ex-vivo) for subsequent gastrointestinal deposition. Oral drug deliverysystems and devices for oral powders are disclosed in WO01/64182, herebyincorporated by reference in its entirety for all purposes.

[0049] In certain embodiments, the invention provides a method ofpreparing a drug delivery system for delivering multiple doses of a drugfor gastrointestinal deposition comprising preparing a fast meltmultiparticulate drug formulation in a manner wherein the drug particleswhen placed in the oral cavity are not deposited in any substantialamount to the lungs; and placing multiple unit doses of the fast meltdrug formulation in a device which meters a single unit dose fordelivery.

[0050] In certain embodiments, the invention provides a method oftreating a patient in need of multiple doses of a drug forgastrointestinal deposition comprising preparing fast meltmultiparticulates in a manner wherein the drug particles when placed inthe oral cavity are not deposited in any substantial amount to the lungsand dissolve or disperse in the mouth within 1 minute afteradministration, placing multiple unit doses of the fast meltmultiparticulates in a device which meters a single unit dose fordelivery and either (a) administering the unit dose into the oral cavityof a patient or(b) dispensing the unit dose into an intermediatereceptacle and thereafter administering the unit dose into the oralcavity of the patient.

[0051] In certain embodiments, the particles of the invention compriseat least about 50% drug; at least about 60% drug; at least about 70%drug; at least about 80% drug; or at least about 90% drug. In others,low doses of up to 20%, 10% or 5% of drug or active agent are carried bythe inventive particles. In certain embodiments, the invention providesa method for delivery of a drug comprising delivering fast meltmultiparticulates comprising drug particles via the use of a multipleunit dosing device comprising a housing and an actuator, the device uponactuation delivering a unit dose of the fast melt multiparticulates, andthereafter re-using the device to deliver additional unit doses of thefast melt multiparticulates at appropriate dosing intervals.

[0052] In preferred embodiments of the invention, the unit dosecomprises a discreet collection of fast melt multiparticulates. Forpurposes of the invention, a “discreet collection” means that the fastmelt multiparticulates are in the form of a non-compressed free flowingunit and not dispersed in a cloud or mist, which effectively minimizesinhalation of the active agent into the lungs of the patient. The unitdose can be include from about 0.01 mg to about 1.5 g of active agent.For example, the dose of active agent can be from about 1 mg to about100 mg, or from about 10 mg to about 50 mg.

[0053] In certain embodiments of the invention, the mean diameter of thefast melt multiparticulates is of a size which minimizes their capacityto be inhaled into the lower lung. Typically, the mean particle size ofthe drug particles (or agglomerates) is greater than 10 μm, preferablygreater than about 50 μm or greater than about 75 μm. In certainembodiments of the invention, the mean particle size range of the drugparticles is from about 100 μm to about 1 mm, preferably from about 50μm to about 500 μm. In preferred embodiments, greater than 80% of theparticles have the above disclosed diameter (not mean diameter), e.g.80% of the drug particles have a diameter of greater than 10 μm, or adiameter of from about 100 μm to about 1 mm. In other embodiments,greater than about 90% of the particles have the above discloseddiameter.

[0054] In certain embodiments of the invention, the mean diameter of thefast melt multiparticulates does not vary by greater than about 20%,preferably not greater than about 15% and most preferably not greaterthan about 10%.

[0055] In certain embodiments of the invention, the multiple doses ofthe fast melt formulation are contained in a reservoir. The reservoircan contain an amount of multiparticulates to provide any number of unitdoses, e.g. from about 2 doses to about 400 doses. For ease in patientcompliance, the reservoir has a sufficient quantity of to provide e.g. adays supply, a months supply or a years supply of doses, e.g. 30 or 365for once daily dosing for a month or year, respectively.

[0056] In order to aid in patient compliance, certain embodiments of theinvention include a counter or indicator to display the number of dosesremaining in the system or the number of doses actuated.

[0057] In certain embodiments of the invention, the unit doses areindividually metered prior to actuation, e.g., in the form of capsulesor blisters or preferably in the form of sachets, wherein each sachetcontains one individual unit dose. The system can be capable ofcontaining any multiple of pre-metered unit doses, e.g. from about 2 toabout 400 sachets.

[0058] For purposes of the present invention, the term “device” refersto an apparatus capable of delivering a unit dose of drug.

[0059] The term “system” refers to a drug delivery device in combinationwith a fast melt multiparticulate formulation having the specificationsdisclosed herein, e.g. drug particle size, excipient type, etc.

[0060] The term “discreet collection” refers to a non-compressed freeflowing unit of multiparticulates with minimal particulate matter beingdispersed in the surrounding environment (e.g., as a cloud or mist).

[0061] The term “drug” refers to any agent which is capable of providinga therapeutic effect to a patient upon gastrointestinal deposition. Thisencompasses all drugs which are intended for absorption for a systemiceffect (regardless of their actual bioavailability) as well as drugsintended for a local effect in the gut and/or oral cavity, e.g.nystatin, antibiotics or local anaesthetics.

[0062] The term “particle size” refers to the diameter of the particle.

[0063] The term “deposition” means the deposit of the unit dose at theintended point of absorption and/or action. For example,gastrointestinal deposition means the intended deposit of the unit dosein the gastrointestinal system for e.g., absorption for a systemiceffect or to exert a local effect. Pulmonary deposition means theintended deposit of drug into the lungs in order to provide apharmaceutical effect, regardless that the unit dose may enter the oralcavity prior to pulmonary deposition.

[0064] The term “dispense”, when used in connection with the devices andsystems of the present invention, means that the device or systemdelivers the unit dose ex vivo with the intent of subsequentadministration to a mammal. For example, the device or system candispense the unit dose into a food, a liquid, a spoon, or anotherintermediate receptacle.

[0065] The term “administer”, when used in connection with the devicesand systems of the present invention, means that the device or systemdelivers the unit dose in vivo, i.e., directly into the gastrointestinaltract of a mammal.

[0066] The term “deliver” is meant to cover all ex vivo and in vivodelivery, i.e., dispensing and administering, respectively.

[0067] The term “patient” refers to humans as well as other mammals inneed of a therapeutic agent, e.g., household pets or livestock. Thisterm also refers to humans or mammals in need of or receivingprophylactic treatment.

[0068] The term “fast melt” means a formulation which dissolving ordisperses in a patient's mouth within 1 minute after administrationwithout the co-administration of a fluid. Preferably, the formulationdissolving or disperses in a patient's mouth within 30 seconds, or 15seconds after administration without the co-administration of a fluid

[0069] The term “disperses” means that the administered formulationbecomes hydrated in the mouth and the particles of the formulationbecome suspended is saliva, such that the multiparticulate formulationis wetted and easily swallowed.

[0070] In certain embodiments, the particulates are defined functionallywith respect to the fact that they are of a size such that an effectivedose cannot be delivered into the lower lung of a human patient.However, this definition should be understood to mean that a smallpercentage of drug (but not an amount effective to render a therapeuticeffect) may in fact be inadvertently delivered to the lungs of thepatient. Also, this definition is meant to define the particles, but notto limit the use of the invention to the treatments of humans only. Theinvention may be used for delivering doses of drugs to other mammals aswell.

[0071] In this specification, there are references to the temperature atwhich the active agent or the water-soluble excipient decomposes. Thistemperature should be understood to be the temperature at and abovewhich the active agent or excipient would decompose to a significantextent, if held there for sufficient time for the active agent orexcipient to be processes by melt granulation.

[0072] In general, it has been recognized in the art that dry powderinhalation or insufflation formulations must consist of particles of asize of about 2 microns in diameter in order for the particles, wheninhaled, to reach the peripheral or “deep” lung, including alveoli.Particles larger than 10 microns in diameter are not able to reach thedeep lung when inhaled because they are collected on the back of thethroat and upper airways in humans. Therefore, known powder deliverysystems have been formulated with particle sizes of less than 10 micronsin order for the particles to reach the intended site of action, thepulmonary system. Known powder delivery devices have not contemplateddelivery of particles from a multi-dose delivery device to achievegastrointestinal deposition, and therefore have avoided the use of drugparticles having a large size, e.g. greater than 10 microns. By virtueof the invention disclosed in Applicants co-pending application,WO01/64182, it has been a surprising discovery that drug particlesgreater than 10 microns can be delivered from a multi-use drug deliverydevice for gastrointestinal deposition in a patient in order to minimizethe inhalation of the drug particles into the lungs, in order to havesubstantially all of the dose deposited in the gastrointestinal system.By virtue of the present invention, powders that can be used in suchdevices can exhibit fast melt properties in order to provide thebenefits of such formulations. The powders can be used in the device orcan be administered without the use of the device, e.g., by using asachet.

[0073] As the fast melt multiparticulates of the present invention arenot intended to be compressed, a high load formulation of the activeagent is ascertainable. This is due to the fact that excipients whichmust be included in prior art fast melt tablets (e.g., fillers in orderto provide bulk for tableting and disintegrants to provide a breakdownof the tablet upon administration) need not be included in the presentformulations, or included to a lesser extent. As the fast meltformulations can have lower excipient and a higher drug load, theresultant unit dose is smaller which decreases the necessary time forthe dissolution or dispersion of the formulation upon oral delivery.

[0074] The water-soluble excipient of the formulation can be a sugaralcohol including, but not limited to sorbitol, mannitol, maltitol,reduced starch saccharide, xylitol, reduced paratinose, erythritol, andcombination thereof. Other suitable water-soluble excipients includegelatin, partially hydrolyzed gelatin, hydrolyzed dextran, dextrin,alginate and mixtures thereof.

[0075] The formulations of the present invention preferably include asalivary stimulant including, but not limited to citric acid, tartaricacid, malic acid, fumaric acid, adipic acid, succinic acid, acidanhydrides thereof, acid salts thereof and combinations thereof.

[0076] The salivary stimulant can also be an effervescent agent, such aswherein the effervescence is the result of a reaction of a soluble acidsource and an alkali metal carbonate or carbonate source. The carbonatesources can be selected from the group consisting of dry solid carbonateand bicarbonate salts such as sodium bicarbonate, sodium carbonate,potassium bicarbonate and potassium carbonate, magnesium carbonate andsodium sesquicarbonate, sodium glycine carbonate, L-lysine carbonate,arginine carbonate and amorphous calcium carbonate.

[0077] The drug formulations of the present invention preferablycomprise a sweetener such as a water-soluble artificial sweetener,including but not limited to soluble saccharin salts, such as sodium orcalcium saccharin salts, cyclamate salts, acesulfam-K, the free acidform of saccharin and mixtures thereof. The sweetener can also comprisea dipeptide based sweetener such as L-aspartyl L-phenylalanine methylester.

[0078] The formulations of the present invention can also comprisefurther pharmaceutical excipients such as polyvinyl alcohol,polyvinylpyrrolidine, acacia or a combination thereof.

[0079] The dissolution or dispersion of the formulation can be improvedwith the use of a surfactant, such as sodium lauryl sulphate (Texapon K12), various polysorbates known under the trade name Tween, ethers ofpolyhydroxy ethylene fatty acids known under the trade name Brij, estersof polyhydroxy ethylene fatty acids known under the trade name Myrj,sodium desoxycholate, glycerol polyethylene glycol ricinoleate(Cremophor EL), polyoxyethylene-polyoxypropylene polymers known underthe trade name Pluronic, and various polyalkoxy alkylene sterol ethers.

[0080] The fast melt formulations of the present invention can alsocomprise starches, e.g., corn starch, or modified starches, e.g., sodiumstarch glycolate or mixtures thereof, in any proportions. Starches canprovide increased salivation due to the porous nature of the starch.Increased salivation favours rapid dissolution or dispersion of theformulation upon oral administration.

[0081] When a starch is present in the formulation, the formulation canfurther comprise a starch degrading enzyme will have a synergisticeffect with the starch with respect to dissolution or dispersion. Theenzymes upon being contacted with an aqueous solution will initiateconversion of the starch to mono and polysaccharides which quicklydissolve in the aqueous environment and further contribute to improvingthe taste of the multiparticulate formulation and increasing salivation.

[0082] The enzymes can be chosen for their degradation effect on thestarch and also for their stability over time, i.e. during theshelf-life of the fast melt multiparticulate formulation.Advantageously, the enzyme will be chosen from the group of starchdegrading enzymes comprising alpha-amylase, beta-amylase,amyloglucosidase, debranching enzymes and glucose-fructose isomerase. Incertain embodiments, the enzymes can be an equal mixture ofamyloglucosidase and a-amylase.

[0083] In certain embodiments, drug formulations in accordance with theinvention are prepared by a process comprising melt granulating thewater soluble excipient and the active agent to form a homogenousmixture. In an alternate embodiment, the process comprises melt coatingthe water-soluble excipient onto the active agent which can beoptionally pregranulated with a pharmaceutically acceptable excipient.

[0084] In such processes, the water-soluble excipient is preferably awater-soluble alcohol such as xylitol.

[0085] The melt granulation and melt coating processes are particularlypreferred processes of the present invention as it is not necessary touse an aqueous fluid as a processing aid. This results in a processwhich can be used for a wide variety of active agents, including thoseagents which would be susceptible to degradation upon contact withwater. Accordingly, such processes provide advantages over many priorart processes for making fast melt systems which rely on water as aprocessing aid. These prior art processes would not be suitable forwater liable drugs as such processes would result in degradation of thedrug during the manufacturing process and during storage due to residualmoisture in the final product.

[0086] In certain embodiments, formulations in accordance with theinvention can be prepared by subliming solvent from a compositioncomprising the active agent and the water soluble excipient and reducingthe sublimed composition to the particles. In such embodiments, thecomposition can further comprises an excipient selected from the groupconsisting of polyvinyl alcohol, polyvinylpyrrolidone, acacia or acombination thereof. The sublimation is preferably by freeze-drying andthe solvent can be an aqueous solvent or a co-solvent comprising anaqueous solvent and an alcohol. A surfactant can also be included insuch a formulation.

[0087] In certain embodiments, fast melt formulations in accordance withthe invention can be prepared by a process which comprises preparing amixture comprising the active agent, the water soluble excipient and asolvent, freezing the mixture, vacuum drying the frozen mixture above acollapse temperature of the mixture to form a partially collapsed matrixnetwork and reducing the sublimed composition to the particles.Preferably, the mixture comprises the active agent, a gum, acarbohydrate base, and a solvent, wherein the gum is selected from thegroup consisting of acacia, guar, xanthan, tragacanth gum, and mixturesthereof, and the carbohydrate is selected from the group consisting ofmannitol, dextrose, sucrose, lactose, maltose, maltodextrin, corn syrupsolids, and mixtures thereof.

[0088] In certain embodiments, fast melt formulations in accordance withthe invention can be prepared by a process which comprises preparing amixture comprising the active agent, the water soluble excipient and anagar aqueous solution, solidifying the mixture into a jelly form, dryingthe jelly and reducing the dried composition into the particles. Thedrying can be effected by reduced pressure drying, aeration drying orfreeze-drying.

[0089] In certain embodiments, fast melt formulations in accordance withthe invention can be prepared by a process which comprises melt spinningthe active agent with the saccharide to form a mass of spun fibres andreducing the spun fibres to the particles. The saccharide can be sucroseor glucose.

[0090] In order to achieve the desired lower limit of the particles sizeof the fast melt multiparticulate formulation of the invention, air jetsieving can be used to remove fine particles. In particular embodiments,the invention is directed to a method of preparing a multiparticulatedrug formulation for gastrointestinal deposition comprising preparing anon-compressed free flowing plurality of particles comprising a corecomprising a drug and a pharmaceutically acceptable excipient asdisclosed herein and air jet sieving the particles to separate the coresfrom fine particles; and thereafter overcoating the core with afunctional coating as disclosed herein.

[0091] The invention is also directed to compositions obtained usingthese methods.

[0092] The compositions of multiparticulates obtained using air jetsieving and methods thereof are not limited to the particularembodiments disclosed herein. The use of an air jet sieve is beneficialas the standard sieving techniques used with screens and meshes may notseparate all of the desired fine particles as the fine particles mayadhere to the surface of larger particles and thus not separate duringthe sieving process. The air jet sieving process utilizes a negativepressure to draw particles below a particular size range down through anappropriate screen or mesh. In another embodiment, there is acombination of a downward negative pressure and an upward positivepressure which facilitates the de-agglomeration of the differentparticle sizes. In other embodiments, the upward pressure can beintroduced upwards from a rotating wand. An apparatus utilizing anegative downward pressure and an upward positive pressure through arotating wand is a Micron Air Jet Sieve MAJS I/II manufactured byHosakawa.

[0093] The effect of humidity can have a negative impact of theflowability of particles (e.g., due to cohesiveness). This can be aparticular problem with the present invention, which is directed to fastmelt multiparticulates which are designed to absorb water. Accordingly,in preferred embodiments, the unit doses of fast melt multiparticulatesare premetered prior to actuation of the device. This reduces thecontamination of the unit doses as compared to having the formulation ina multiple dose reservoir. Preferably, the premetered unit doses arecontained in sachets which minimize the effect of humidity and moistureon the formulation.

[0094] Other multiple unit oral dosing devices, adapted contain theformulation in a reservoir or as premetered unit doses, which are usefulin the present invention are disclosed in WO01/64182 hereby incorporatedby reference.

[0095] Classes of drugs which are suitable in the present inventioninclude antacids, anti-inflammatory substances, coronary dilators,cerebral dilators, peripheral vasodilators, anti-infectives,psychotropics, anti-manics, stimulants, anti-histamines, laxatives,decongestants, vitamins, gastrointestinal sedatives, anti-diarrhealpreparations, anti-anginal drugs, vasodilators, anti-arrhythmics,anti-hypertensive drugs, vasoconstrictors and migraine treatments,anti-coagulants and anti-thrombotic drugs, analgesics, anti-pyretics,hypnotics, sedatives, anti-emetics, anti-nauseants, anti-convulsants,neuromuscular drugs, hyper- and hypoglycemic agents, thyroid andanti-thyroid preparations, diuretics, anti-spasmodics, uterinerelaxants, mineral and nutritional additives, anti-obesity drugs,anabolic drugs, erythropoietic drugs, anti-asthmatics, bronchodilators,expectorants, cough suppressants, mucolytics, drugs affectingcalcification and bone turnover and anti-uricemic drugs. Specific drugsinclude gastro-intestinal sedatives such as metoclopramide andpropantheline bromide; antacids such as aluminum trisilicate, aluminumhydroxide, ranitidine and cimetidine; anti-inflammatory drugs such asphenylbutazone, indomethacin, naproxen, ibuprofen, flurbiprofen,diclofenac, dexamethasone, prednisone and prednisolone; coronaryvasodilator drugs such as glyceryl trinitrate, isosorbide dinitrate andpentaerythritol tetranitrate; peripheral and cerebral vasodilators suchas soloctidilum, vincamine, naftidrofuryl oxalate, co-dergocrinemesylate, cyclandelate, papaverine and nicotinic acid; anti-infectivesubstances such as erythromycin stearate, cephalexin, nalidixic acid,tetracycline hydrochloride, ampicillin, flucloxacillin sodium, hexaminemandelate and hexamine hippurate; neuroleptic drugs such as flurazepam,diazepam, temazepam, amitryptyline, doxepin, lithium carbonate, lithiumsulfate, chlorpromazine, thioridazine, trifluperazine, fluphenazine,piperothiazine, haloperidol, maprotiline hydrochloride, imipramine anddesmethylimipramine; central nervous stimulants such as methylphenidate,ephedrine, epinephrine, isoproterenol, amphetamine sulfate andamphetamine hydrochloride; antihistamic drugs such as diphenhydramine,diphenylpyraline, chlorpheniramine and brompheniramine; anti-diarrhealdrugs such as bisacodyl and magnesium hydroxide; the laxative drug,dioctyl sodium sulfosuccinate; nutritional supplements such as ascorbicacid, alpha tocopherol, thiamine and pyridoxine; anti-spasmodic drugssuch as dicyclomine and diphenoxylate; drugs affecting the rhythm of theheart such as verapamil, nifedipine, diltiazem, procainamide,disopyramide, bretylium tosylate, quinidine sulfate and quinidinegluconate; drugs used in the treatment of hypertension such aspropranolol hydrochloride, guanethidine monosulphate, methyldopa,oxprenolol hydrochloride, captopril and hydralazine; drugs used in thetreatment of migraine such as ergotamine; drugs affecting coagulabilityof blood such as epsilon aminocaproic acid and protamine sulfate;analgesic drugs such as acetylsalicylic acid, acetaminophen, codeinephosphate, codeine sulfate, oxycodone, dihydrocodeine tartrate,oxycodeinone, morphine, heroin, nalbuphine, butorphanol tartrate,pentazocine hydrochloride, cyclazacine, pethidine, buprenorphine,scopolamine and mefenamic acid; anti-epileptic drugs such as phenytoinsodium and sodium valproate; neuromuscular drugs such as dantrolenesodium; substances used in the treatment of diabetes such astolbutamide, disbenase glucagon and insulin; drugs used in the treatmentof thyroid gland dysfunction such as triiodothyronine, thyroxine andpropylthiouracil, diuretic drugs such as furosemide, chlorthalidone,hydrochlorthiazide, spironolactone and triamterene; the uterine relaxantdrug ritodrine; appetite suppressants such as fenfluraminehydrochloride, phentermine and diethylproprion hydrochloride;anti-asthmatic and bronchodilator drugs such as aminophylline,theophylline, salbutamol, orciprenaline sulphate and terbutalinesulphate; expectorant drugs such as guaiphenesin; cough suppressantssuch as dextromethorphan and noscapine; mucolytic drugs such ascarbocisteine; anti-septics such as cetylpyridinium chloride,tyrothricin and chlorhexidine; decongestant drugs such asphenylpropanolamine and pseudoephedrine; hypnotic drugs such asdichloralphenazone and nitrazepam; anti-nauseant drugs such aspromethazine theoclate; haemopoietic drugs such as ferrous sulphate,folic acid and calcium gluconate; uricosuric drugs such assulphinpyrazone, allopurinol and probenecid; and calcification affectingagents such as biphosphonates, e.g., etidronate, pamidronate,alendronate, residronate, teludronate, clodronate and alondronate.

[0096] Particularly preferred agents include antibiotics such asclarithromycin, amoxicillin erythromycin, ampicillin, penicillin,cephalosporins, e.g., cephalexin, pharmaceutically acceptable saltsthereof and derivatives thereof.

[0097] A particularly preferred agent is paracetamol (acetaminophen).Other preferred agents are NTHES such as ibuprofen, indomethacin,aspirin, diclofenac and pharmaceutically acceptable salts thereof.

[0098] In certain preferred embodiments, however, formulations inaccordance with the invention do not include any non-steroidalanti-inflammatory drug (NSAID).

[0099] The size of the unit dose is dependent on the amount of drugneeded to provide the intended therapeutic effect and the amount of anypharmaceutically acceptable excipient which may be necessary. Typically,a unit dose of from about 0.01 mg to about 1.5 g would be sufficient tocontain a therapeutically effective amount of the drug to be delivered,however, this range is not limiting and can be smaller or higher,depending on the amount of drug and excipient that is necessary.

[0100] The following examples serve to illustrate the invention, butshould not be understood to be limiting in any respect.

EXAMPLE 1

[0101] The following materials were employed in this example. Material %Composition Paracetamol 75 Xylitol 24 Aspartame 0.5 Acesulphame K 0.5

[0102] Method

[0103] Granular paracetamol, aspartame fine, acesulphame potassium and12% xylitol were accurately weighed into a glass jar and blended at 42rpm for 30 minutes using an inversion low shear mixer. The blend wastransferred to a jacketed vessel maintained at a temperature of 95° C.The blend was mixed at an impeller speed sufficient to keep the wholepowder bed moving (i.e. 222 RPM) using an overhead mixer for a timesufficient to allow homogenous distribution of the molten binder in theblend. The remaining melt binder was added to the blend and the impellerspeed increased to provide continuous movement of the powder bed (i.e.250 RPM). The formulation was cooled and then sieved using a 710 micronsieve to remove any large agglomerates, once distribution of the meltbinder was complete.

[0104] Results

[0105] The formulation had a sweet taste and good mouthfeel. Thedissolution of the paracetamol from the formulation was measured using amodified version of the standard USP test for measuring paracetamol(acetaminophen) dissolution. The test conditions involved stirring 333mg of the formulation in 900 ml of water, buffered to pH 5.8 with apotassium phosphate buffer, at 37° C., using a paddle speed of 100 RPM(the standard USP paddle speed is 50 RPM). The results are set outbelow.

EXAMPLE 2

[0106] The following materials were employed in this example. Material %Composition Paracetamol 77 Xylitol 20 Aspartame 0.5 Acesulphame K 0.5Maltodextrin M100 2

[0107] Method

[0108] Granular paracetamol, aspartame fine, maltodextrin M100,acesulphame potassium and 10% xylitol were accurately weighed into aglass jar and blended at 42 rpm for 30 minutes using an inversion lowshear mixer. The blend was transferred to a jacketed vessel maintainedat a temperature of 95° C. The blend was mixed at an impeller speedsufficient to keep the whole powder bed moving (i.e. 222 RPM) using anoverhead mixer for a time sufficient to allow homogenous distribution ofthe molten binder in the blend. The remaining melt binder was added tothe blend and the impellar speed increased to provide continuousmovement of the powder bed (i.e. 250 RPM). The formulation was cooledand then sieved using a 710 micron sieve to remove any largeagglomerates, once distribution of the melt binder was complete.

[0109] Results

[0110] It was found that incorporation of certain grades maltodextrinimproved mouthfeel and reduced aftertaste without impeding drug release.The dissolution of the paracetamol from the formulation was measuredusing the same test as that employed in Example 1, and the results areset out below.

EXAMPLE 3

[0111] The tastemasking properties of xylitol result from its negativeheat of solution, which confers a cooling effect on dissolution on theoral cavity. This example details the use of erythritol, which has agreater negative heat of solution, to improve the degree oftastemasking. Formulations were prepared using erythritol as the meltbinder from the following materials. Material % Composition Paracetamol87 Erythritol 10 Aspartame 0.5 Acesulphame K 0.5 Maltodextrin M100 2

[0112] Method

[0113] Granular paracetamol, aspartame fine, maltodextrin M100,acesulphame potassium and 5% erythritol were accurately weighed into aglass jar and blended at 42 rpm for 30 minutes using an inversion lowshear mixer. The blend was transferred to a jacketed vessel maintainedat a temperature of 121° C. The blend was mixed at an impellar speedsufficient to keep the whole powder bed moving (i.e. 222 RPM) using anoverhead mixer for a time sufficient to allow homogenous distribution ofthe molten binder in the blend. The remaining melt binder was added tothe blend and the impellar speed increased to provide continuousmovement of the powder bed (i.e. 250 RPM). The formulation was cooledand then sieved using a 710 micron sieve to remove any largeagglomerates, once distribution of the melt binder was complete.

[0114] Results

[0115] Upon melt granulation it was observed that the formulationdeveloped a slight brown discoloration. This was attributed to thethermal degredation of Maltodextrin M100. This was confirmed by thepreparation of Example 4 in which there was no evidence of browning.

EXAMPLE 4

[0116] The following materials were employed in this example. Material %Composition Paracetamol 89 Erythritol 10 Aspartame 0.5 Acesulphame K 0.5

[0117] Method

[0118] Granular acetaminophen, aspartame fine, acesulphame potassium and5% erythritol were accurately weighed into a glass jar and blended at 42rpm for 30 minutes using an inversion low shear mixer. The blend wastransferred to a jacketed vessel maintained at a temperature of 121° C.The blend was mixed at an impeller speed sufficient to keep the wholepowder bed moving (i.e. 222 RPM using an overhead mixer for a timesufficient to allow homogenous distribution of the molten binder in theblend. The remaining melt binder (erythritol) was added to the blend andthe impeller speed increased to provide continuous movement of thepowder bed (i.e. 250 RPM). The formulation was cooled and then sievedusing a 710 micron sieve to remove any large agglomerates, oncedistribution of the melt binder was complete.

[0119] Dissolution profiles were not obtained for examples 3 and 4.

EXAMPLE 5

[0120] The following materials were employed in this example. Material %Composition Paracetamol 82 Erythritol 5 Xylitol 10 Maltodextrin M100 2Aspartame 0.5 Acesulphame K 0.5

[0121] Method

[0122] Granular acetaminophen and erythritol were accurately weighedinto a glass jar and blended at 42 rpm for 30 minutes using an inversionlow shear mixer. The blend was transferred to a jacketed vesselmaintained at a temperature of 121° C. The blend was mixed at animpeller speed sufficient to keep the whole powder bed moving (i.e. 222RPM) using an overhead mixer for a time sufficient to allow homogenousdistribution of the molten binder in the blend. The temperature was thenreduced to 95° C. and the xylitol, aspartame fine, acesulphame potassiumand maltodextrin added to the blend. The impeller speed was increased asrequired to provide continuous movement of the powder bed (i.e. 250RPM). The formulation was cooled and then sieved using a 710 micronsieve to remove any large agglomerates, once distribution of the meltbinder was complete.

[0123] Results

[0124] Example 5 exhibited improved tastemasking over example 2, withimproved masking of the slight aftertaste which was evident in example 3and minimal evidence of the aftertaste which was evident in example 4.The browning of the formulation which was observed in example 3 was notevident in this formulation due to the incorporation of maltodextrin inthe second stage of melt coating. The dissolution of the paracetamolfrom the formulation was measured using the same test as that employedin Example 1, and the results are set out below.

[0125] The drug release profiles of the formulation of Example 5 versusthat of the unformulated raw drug, i.e., granular acetaminophen, areshown in FIG. 1. The particle size distributions of the formulation ofExample 5 (“Special Granulate APAP”) versus that of the unformulated rawdrug (“Paracetamol Special Granular”) are shown in FIG. 2.

EXAMPLE 6

[0126] Example 6 describes the use of materials capable of liberatingcarbon dioxide in aqueous conditions to facilitate tastemasking. Thefollowing materials were employed in this example. Material %Composition Paracetamol 77 Xylitol 20 Sodium Glycine Carbonate 1.2Citric Acid Monohydrate 0.8 Acesulphame K 0.5 Aspartame 0.5

[0127] Method

[0128] Granular paracetamol, aspartame fine, sodium glycine carbonate,citric acid monohydrate, acesulphame potassium and 10% xylitol wereaccurately weighed into a glass jar and blended at 42 rpm for 30 minutesusing an inversion low shear mixer. The blend was transferred to ajacketed vessel maintained at a temperature of 95° C. The blend wasmixed at an impellar speed sufficient to keep the whole powder bedmoving (i.e. 222 RPM using an overhead mixer for a time sufficient toallow homogenous distribution of the molten binder in the blend. Theremaining melt binder was added to the blend and the impellar speedincreased to provide continuous movement of the powder bed (i.e. 250RPM. The formulation was cooled and then sieved using a 710 micron sieveto remove any large agglomerates, once distribution of the melt binderwas complete.

[0129] Results

[0130] The formulation exhibited acceptable tastemasking. However, theaddition of Maltodextrin M100, as shown in example 7, improved itsmouthfeel.

EXAMPLE 7

[0131] The following materials were employed in this example. Material %Composition Paracetamol 77 Xylitol 18 Maltodextrin M100 2.0 SodiumGlycine Carbonate 1.2 Citric Acid Monohydrate 0.8 Acesulphame K 0.5Aspartame 0.5

[0132] Method

[0133] Granular paracetamol, aspartame fine, sodium glycine carbonate,citric acid monohydrate, maltodextrin M100, acesulphame potassium and 9%xylitol were accurately weighed into a glass jar and blended at 42 rpmfor 30 minutes using an inversion low shear mixer. The blend wastransferred to a jacketed vessel maintained at a temperature of 95° C.The blend was mixed at an impeller speed sufficient to keep the wholepowder bed moving (i.e. 222 RPM) using an overhead mixer for a timesufficient to allow homogenous distribution of the molten binder in theblend. The remaining melt binder was added to the blend and the impellerspeed increased to provide continuous movement of the powder bed (i.e.250 RPM). The formulation was cooled and then sieved using a 710 micronsieve to remove any large agglomerates, once distribution of the meltbinder was complete.

[0134] Results

[0135] The addition of Maltodextrin M100 was shown to improve mouthfeel.

EXAMPLE 8

[0136] Example 8 illustrates the use of polyethylene glycols (PEGs) asthe water soluble melt binder.

[0137] The following materials were employed in this example. Material %Composition Paracetamol 80 Erythritol 5 PEG6000 Powder 10 MaltodextrinM100 2.0 Sodium Glycine Carbonate 1.2 Citric Acid Monohydrate 0.8Acesulphame K 0.5 Aspartame 0.5

[0138] Method

[0139] Granular paracetamol, erythritol, sodium glycine carbonate andcitric acid monohydrate and 5% PEG6000 were accurately weighed into aglass jar and blended at 42 rpm for 30 minutes using an inversion lowshear mixer. The blend was transferred to a jacketed vessel maintainedat a temperature of 70° C. The blend was mixed at an impeller speedsufficient to keep the whole powder bed moving (i.e. 222 RPM) using anoverhead mixer for a time sufficient to allow homogenous distribution ofthe molten binder in the blend. The remaining melt binder was added tothe blend, along with the maltodextrin M100, aspartame and acesulphamepotassium, and the impeller speed increased to provide continuousmovement of the powder bed (i.e. 250 RPM). The formulation was cooledand then sieved using a 710 micron sieve to remove any largeagglomerates, once distribution of the melt binder was complete.

[0140] Results

[0141] The resulting formulation exhibited reasonable tastemasking and aslight aftertaste, but with excellent mouthfeel and rapiddispersibility.

EXAMPLE 9

[0142] An additional approach to drug tastemasking is described wherethe citric acid monohydrate content is increased to locally modify thepH within the oral cavity and therefore limit drug dissolution.

[0143] The following materials were employed in this example. Material %Composition Paracetamol 77.2 Erythritol 10.0 PEG6000 Powder 7.0 Sodiumstarch Glycolate 2.0 Sodium Glycine Carbonate 1.2 Citric AcidMonohydrate 1.5 Acesulphame K 0.5 Aspartame 0.5 Powdered Lemon Flavour0.1

[0144] Method

[0145] Using a Diosna P1-6 mixer-granulator equipped with a 1 litrejacketed bowl was heated at 55° C. for 10 minutes before the addition ofthe granular acetaminophen, erythritol, sodium starch glycolate, sodiumglycine carbonate, citric acid monohydrate, aspartame fine, acesulphamepotassium and powdered lemon flavour. This material was blended for afurther 10 minutes prior to the addition of the PEG6000. An impellerspeed of 50 RPM and a chopper speed of 50 RPM were selected todistribute the binder through the material. Mixing was continued at theelevated temperature for approximately 5 minutes before the bowl wascooled to 25° C. for 10 minutes.

[0146] Results

[0147] The resulting formulation exhibited pleasant taste, goodmouthfeel and a slight bitter aftertaste; which is attributed to thepresence of additional citric acid. The dissolution of the paracetamolfrom the formulation was measured using the same test as that employedin Example 1, and the results are set out below.

EXAMPLE 10

[0148] Sumatriptan 50 mg (Final Formulation Mass 75.7 mg) A granulationof Sumatriptan was prepared containing 4% w/w PVP K-30 (aqueous) in a MPMicro fluid bed dryer. The drug and binder were granulated by theaddition of water, using the down-spray method. The granulated materialwas dried, cooled and then screened through a 250 μm sieve and airjetsieved to remove particles below 1001 m. The resulting granules werethen spray coated with an aqueous dispersion of Eudragit RD-100plasticised with Triacetin. The quantity of coating was sufficient toachieve the required degree of tastemasking of the active (approximately15% weight gain). The granules were then dried and cooled for hot meltcoating with xylitol. The tastemasked Sumatriptan granules were loadedinto a 1 litre-jacketed bowl for a modified Diosna P1-6 mixer-granulator(preheated at 95° C. for 10 minutes) with 1% Aspartame (or 0.5%Aspartame and 0.5% Acesulfame potassium) and 10% xylitol. An impellerspeed of 50 RPM and a chopper speed of 50 RPM were selected todistribute the binder (xylitol) through the material. Mixing wascontinued at the elevated temperature for approximately 5 minutes beforeaddition of a further 10% xylitol to the system. After another 5 minutesmixing, the bowl was cooled to 25° C. over 10 minutes. Once cooled theformulation was tested. It was found that improved tastemasking and drugrelease could be achieved by further addition of Triacetin to theEudragit RD100 film coat.

EXAMPLE 11

[0149] Lansoprazole 15 mg (Final Formulation Mass 20 mg)

[0150] Using a Diosna P1-6 mixer-granulator, a melt-granulation of 75%Lansoprazole, 20% PEG 6000 and 5% Aspartame was prepared using a onelitre jacketed mixing bowl heated to a temperature sufficient to meltthe PEG 6000 binder (i.e. 70° C.). The Lansoprazole and Aspartame wereequilibrated in the bowl for 10 minutes at an impeller speed of 300 RPMand a chopper speed of 150 RPM, after this time the PEG6000 was addedand massing continued for another 3 minutes. The material was thenemptied from the bowl, cooled on a metal tray at room temperature andthen stored in sealed bags. It was found that incorporation of 5% of alow-viscosity Sodium Starch Glycolate into the granules improved themouthfeel of this formulation without altering drug release or thedegree of tastemasking.

EXAMPLE 12

[0151] Ranitidine 150 mg (Final Formulation Mass 200 mg)

[0152] Using a Diosna P1-6 mixer-granulator, a melt-granulation of 75%Ranitidine, 20% PEG 6000 and 5% Aspartame was prepared using a one litrejacketed mixing bowl heated to a temperature sufficient to melt the PEG6000 binder (i.e. 70° C.). The Ranitidine and Aspartame wereequilibrated in the bowl for 10 minutes at an impeller speed of 300 RPMand a chopper speed of 150 RPM, after this time the PEG6000 was addedand massing continued for another 3 minutes. The material was thenemptied from the bowl, cooled on a metal tray at room temperature andthen stored in sealed bags. It was found that incorporation of molarequivalents of citric acid monohydrate and sodium bicarbonate into themelt granulation improved the degree of tastemasking and aided thedispersion of the granules.

EXAMPLE 13

[0153] Domperidone 10 mg (Final Formulation Mass 100 mg)

[0154] A 5% w/w aqueous dispersion of maltodextrin containing 5% w/wdomperidone was prepared and spray-coated onto microcrystallinecellulose spheres sufficient to achieve a 33% coating wt. gain using andMP-Micro Fluid Bed Dryer. The coated spheres were then dried and cooledfor hot melt coating with xylitol. Using a modified Diosna P1-6mixer-granulator the domperidone-loaded microcrystalline cellulosespheres were blended with 10% wt. gain of xylitol using a one litrejacketed mixing bowl heated to 95° C. An impeller speed of 50 RPM and achopper speed of 50 RPM were selected to distribute the binder throughthe material. Mixing was continued at the elevated temperature forapproximately 5 minutes before addition of a further 10% xylitol to thesystem. After another 5 minutes mixing, the bowl was cooled to 25° C.over 10 minutes. Once cooled, the formulation was tested. It was foundthat the incorporation of 0.25-0.5% of hydroxypropylmethylcellulose tothe xylitol improved the stability of the formulation.

EXAMPLE 14

[0155] Paracetamol (Acetaminophen) 500 mg (Final Formulation Mass 745mg)

[0156] Step 1: Spray Coating With Surelease

[0157] Granular paracetamol was tastemasked by spray-coating with anaqueous dispersion of ethylcellulose in an MP-Micro Fluid Bed Dryer.Approximately a 15% wt. gain was required, depending on the degree oftastemasking. Once the desired weight of ethylcellulose had been addedto the granules, the material was dried, cooled and then screenedthrough a 250 μm sieve and airjet sieved to remove particles below 100μm. Using a modified Diosna P1-6 mixer-granulator, the tastemaskedparacetamol granules were then blended with 1% Aspartame and 10% xylitolin a one litre jacketed mixing bowl heated to 95° C. for 10 minutes. Animpeller speed of 50 RPM and a chopper speed of 50 RPM were selected todistribute the binder through the material. Mixing was continued at theelevated temperature for approximately 5 minutes before addition of afurther 10% xylitol to the system. After another 5 minutes mixing thebowl was cooled to 25° C. over 10 minutes. Once cooled the formulationwas tested. It was found that improved tastemasking and drug releasecould be achieved by further addition of glycerol to the ethylcellulosefilm coat.

EXAMPLE 15

[0158] Loperamide 2 mg (Final Formulation Mass 50 mg)

[0159] A granulation of equal quantities of aspartame and Acesulphame Kwas prepared using 4% w/w PVP K-30 (aqueous) in a MP Micro fluid beddryer. The drug and binder were granulated by the addition of water,using the down-spray method. The granulated material was dried, cooledand then screened through a 250 μm sieve and airjet sieved to removeparticles below 100 μm. The granules were dried and cooled for hot meltcoating with xylitol. Using a modified Diosna P1-6 mixer-granulator theaspartame/acesulphame K granules were blended with 4% Loperamide and 10%wt. gain of xylitol using a one litre jacketed mixing bowl heated to 95°C. An impeller speed of 50 RPM and a chopper speed of 50 RPM wereselected to distribute the binder through the material. Mixing wascontinued at the elevated temperature for approximately 5 minutes beforeaddition of a further 10% xylitol to the system. After another 5 minutesmixing the bowl was cooled to 25° C. over 10 minutes. Once cooled theformulation was tested. It was found that the incorporation of 0.25-0.5%of hydroxypropylmethylcellulose to the xylitol improved the stability ofthe formulation.

EXAMPLE 17

[0160] Co-Beneldopa 12.5 mg/50 mg (Final Formulation Mass 164.8 mg)

[0161] A granulation of 19.2% Benserazide Hydrochloride and 76.8%Levodopa was prepared using 4% w/w PVP K-30 (aqueous) in a MP Microfluid bed dryer. The drug and binder were granulated by the addition ofwater, using the down-spray method. The granulated material was dried,cooled and then screened through a 250 μm sieve and airjet sieved toremove particles below 100 μm. The granules were dried and cooled forhot melt coating with Xylitol. Using a modified Diosna P1-6mixer-granulator the Co-Beneldopa granulation was blended with 10%xylitol in a one litre jacketed mixing bowl heated to 95° C. for 10minutes. An impeller speed of 50 RPM and a chopper speed of 50 RPM wereselected to distribute the binder through the material. Mixing wascontinued at the elevated temperature for approximately 5 minutes beforeaddition of a further 10% xylitol to the system.

[0162] After another 5 minutes mixing the bowl was cooled to 25° C. over10 minutes. Once cooled the formulation was tested. It was found that byadding a 5% wt. gain of glyceryl palmitostearate and 1% wt. gain ofaspartame, the degree of tastemasking was improved without adverselyimpeding drug release.

EXAMPLE 18

[0163] Enteric coated Aspirin formulation

[0164] Method

[0165] Granular Aspirin, having a particle size suitable for spraycoating (i.e., between 100 and 5001 μm) was coated in an MP-Micro fluidbed dryer, using the down-spray coating module. An aqueous dispersion of15% w/w Opadry® was prepared, which was sprayed onto the granularaspirin at a product temperature of between 40 and 45° C. to a weightgain of 10%. The coated material was dried before a 15% weight gain ofan aqueous dispersion of 15% w/w Acryl-eze was added to the granules, ata product temperature of 25-35° C. The material was dried and cooledbefore being placed in a one litre jacketed bowl for the Diosna P1-6mixer granulator. A blend of 60% enteric coated aspirin, 20% Mannitol,10% Xyltiol 7% Peg 6000, 0.5% Aspartame, 0.5% Acesulfame Potassium and2% Maltodextrin was equilibrated at 70° C. whilst mixing at an impellarspeed of 50 RPM and a chopper speed of 50 RPM. Mixing was continued atthe elevated temperature for approximately 5 minutes before the bowl wascooled to 25° C. for 10 minutes.

[0166] Results

[0167] The formulation met USP requirements for acid phase drug release,i.e., less than or equal to 10% dissolved in 2 hours in 0.1M HCl andgreater than 80% released in 90 minutes in pH 6.8 phosphate buffer.

EXAMPLE 19

[0168] Controlled Release Chlorpheniramine Maleate Drug-Loaded Spheres

[0169] Step 1: Drug Loading

[0170] Chlorpheniramine maleate was dissolved in an aqueous dispersionof 10% Opadry®. A 15% weight gain of Opadry® was applied to 60-40 meshnon-pariel sugar spheres, in order to obtain an active drug content ofapproximately 8% w/w. The dispersion was applied to the sugar spheres ata product temperature of between 40 and 45° C. in an MP-Micro fluid beddryer, using the down-spray coating module.

[0171] Step 2: Sustained Release Coating

[0172] An additional 5% coat of 10% Opadry® aqueous dispersion was addedto the drug loaded spheres before the application of an aqueousdispersion of 15% w/w Surelease was applied. A weight gain of between 15and 30% was applied to produce a formulation with the required releaseprofile.

[0173] Step 3: Melt Granulation

[0174] The dried, 65% drug-loaded spheres were blended in a one litrejacketed bowl for the Diosna P1-6 mixer granulator with 15% Mannitol,10% Erythritol, 7% Peg 6000, 0.5% Aspartame, 0.5% Acesulfame Potassiumand 2% Maltodextrin and equilibrated at 70° C. whilst mixing at animpellar speed of 50 RPM and a chopper speed of 50 RPM. Mixing wascontinued at the elevated temperature for approximately 5 minutes beforethe bowl was cooled to 25° C. for 10 minutes.

[0175] Results Time (Hours) % Drug Release 2 20-30 4 35-45 6 45-55 1260-70

EXAMPLE 20

[0176] Immediate release Chlorpheniramine Maleate

[0177] A granulation of 8% Chlorpheniramine Maleate, 4% w/w PVP K-30 and88% Xylitol was prepared in an MP Micro fluid bed dryer. The materialswere granulated by the addition of water, using the down-spray method.The granulated material was dried, cooled and then screened through a250 μm sieve and airjet sieved to remove particles below 1001 μm. Ablend containing 50% Chlorpheniramine Granules, 25% Granular Mannitol,10% Erythritol, 0.5% Aspartame, 0.5% Acesulfame Potassium, 1.2% CitricAcid Monohydrate, 0.8% Sodium Glycine Carbonate and 2% Maltodextrin wasequilibrated at 70° C. in a one litre jacketed bowl for a Diosna P1-6mixer-granulator for 10 minutes at an impellar speed of 50 RPM and achopper speed of 50 RPM prior to the addition of 10% PEG6000. Mixing wascontinued at the elevated temperature for approximately 5 minutes beforethe bowl was cooled to 25° C. for 10 minutes.

EXAMPLE 21

[0178] 10 Chronotherapeutic Chlorpheniramine Maleate Blend Method

[0179] A blend of 16.7 g of immediate-release chlorpheniramine maleategranules (Example 20) was blended with 83.3 g controlled-releasechlorpheniramine maleate drug-loaded spheres (Example 19) at 42 rpm for30 minutes using an inversion low shear mixer. Results (Formulation mass600 mg: active 24 mg) Time (Hours) Mean Drug Release (mg) n = 6 0.5 4.24 9.6 6 12.1 12 15.6

1. A drug formulation for gastrointestinal deposition, said formulationcomprising a free flowing plurality of particles comprising an activeagent and a water-soluble excipient, wherein the particles have a meandiameter of greater than about 10 μm to about 1 mm, and the formulationis capable of dissolving or dispersing in a patient's mouth within 1minute after administration without the co-administration of a fluid. 2.A drug formulation for gastrointestinal deposition, said formulationcomprising a free flowing plurality of particles and including an activeagent and a water-soluble excipient, wherein the particles have a meandiameter of greater than about 10 μm to about 1 mm, and the excipienthas a negative heat of solution.
 3. A drug formulation as claimed inclaim 2, wherein said particles each include both active agent andwater-soluble excipient.
 4. A drug formulation as claimed in claim 3,wherein the particles comprise a core and a coating that includes aquantity of the excipient.
 5. A drug formulation as claimed in claim 1,wherein the particles are formed by melt-coating core particles with acoating material that includes a quantity of the excipient, at atemperature below the melting point or decomposition temperature of theactive agent.
 6. A drug formulation as claimed in claim 4, wherein aquantity of the active agent is included in the core or core particles.7. A drug formulation as claimed in claim 6, wherein the coating orcoating material is substantially free of active agent.
 8. A drugformulation as claimed in claim 4, wherein a quantity of the activeagent is included in the coating or coating material.
 9. A drugformulation as claimed in claim 8, wherein the core or core particlesare substantially free of active agent.
 10. A drug formulation asclaimed in claims 4, wherein the coating or coating material furthercomprises a water soluble or hydrophilic binder.
 11. A drug formulationas claimed in claim 10, wherein the binder melts or softens sufficientlyto melt-coat the core particles at a temperature below the melting pointor decomposition temperature of the active agent.
 12. A drug formulationas claimed in claim 1, wherein the excipient melts or softenssufficiently to melt-coat the core particles at a temperature below themelting point or decomposition temperature of the active agent.
 13. Adrug formulation as claimed in claim 11, wherein the binder melts orsoftens sufficiently to melt-coat the core particles at a temperaturebelow the melting point or decomposition temperature of the excipient.14. A drug formulation as claimed in claims 4, wherein the coating orcoating material substantially completely covers the surface of the coreor core particles.
 15. A drug formulation as claimed in claim 1, whereinthe core or core particles include a quantity of the water-solubleexcipient and/or an additional, optionally, water soluble excipient. 16.A drug formulation as claimed in claim 15, wherein, the core or eachcore particle comprises a granulation of said an additional excipientand active agent, or a particle of additional excipient coated withactive agent.
 17. A drug formulation as claimed in claim 1, formed by aprocess in which the active agent is not raised to or above its meltingpoint, or a temperature at which a significant proportion thereof iscaused to decompose.
 18. A drug formulation as claimed in claim 1,wherein the melting point of the water-soluble excipient is equal to orbelow 150, 120 or 110° C.
 19. A drug formulation as claimed in claim 18,wherein the melting point of the water-soluble excipient is at least 40or 50° C.
 20. A drug formulation as claimed in claim 1, wherein themelting point of the binder is equal to or below 150, 120 or 110° C. 21.A drug formulation as claimed in claim 20, wherein the melting point ofthe binder is at least 40 or 50° C.
 22. A drug formulation as claimed inclaim 1, wherein the melting point of the excipient exceeds that of thebinder.
 23. A drug formulation as claimed in claim 1, wherein thewater-soluble excipient has a heat of solution equal to or below −7KCal/Kg.
 24. A drug formulation as claimed in claim 23, wherein the heatof solution of the water-soluble excipient is equal to or below −10,—15, −20, −25, or −30 KCal/Kg.
 25. A drug formulation as claimed inclaim 1, wherein the solubility in water of the water-soluble excipientis at least 20, 30 or 40% w/w at 25° C.
 26. A drug formulation asclaimed in claim 1, wherein the water-soluble excipient is a sugar,sugar alcohol, polyethylene glycol (PEG), polyethylene oxide, gelatin,partially hydrolyzed gelatin, hydrolyzed dextran, dextrin, alginate or amixture of any of the foregoing.
 27. A drug formulation as claimed inclaim 26, wherein the water-soluble excipient is a sugar alcohol orcombination of sugar alcohols.
 28. A drug formulation as claimed inclaim 27, wherein the sugar alcohol or sugar alcohols is or aresorbitol, mannitol, maltitol, reduced starch saccharide, xylitol,reduced paratinose, erythritol, or any combination thereof.
 29. A drugformulation as claimed in claim 1, wherein the binder includes apolyethylene glycol (PEG) and/or a polyethylene oxide.
 30. A drugformulation as claimed in claim 1, wherein the core or core particlesinclude an additional excipient for controlling or delaying the releaseof the active agent.
 31. A drug formulation as claimed in claim 30,wherein the core or core particles include a layer or coating of saidadditional excipient encapsulating an inner core comprising the activeagent.
 32. A drug formulation as claimed in claim 30, wherein saidadditional excipient provides an enteric or sustained release coating.33. A drug formulation as claimed in claim 32, wherein said additionalexcipient is selected from the group consisting of cellulose acetatephthalate, hydroxypropyl-methylcelluose phthalate, polymethacrylates,Shellac, ethylcellulose, hydroxypropyl-celluose, andhydroxypropylmethylcelluose.
 34. A drug formulation as claimed in claim1, wherein said formulation dissolves in a patient's mouth within 30 or15 seconds after administration without the coadministration of a fluid.35. A drug formulation as claimed in claim 1, wherein the particlescomprise at least about 50%, 60%, or 75% drug.
 36. A drug formulation asclaimed in claim 1 further comprising a salivary stimulant.
 37. A drugformulation as claimed in claim 1, wherein said formulation furthercomprises an excipient selected from the group consisting of polyvinylalcohol, polyvinylpyrrolidine, acacia and combinations thereof.
 38. Adrug formulation as claimed in claim 1 further comprising awater-soluble artificial sweetener.
 39. A drug formulation as claimed inclaim 38, wherein said water soluble artificial sweetener is selectedfrom the group consisting of soluble saccharin salts, such as sodium orcalcium saccharin salts, cyclamate salts, acesulfam-K, the free acidform of saccharin and mixtures thereof.
 40. A drug formulation asclaimed in claim 1 further comprising a dipeptide based sweetener.
 41. Adrug formulation as claimed in claim 40, wherein said dipeptide basedsweetener is L-aspartyl L-phenylalanine methyl ester.
 42. A drugformulation as claimed in claim 36, wherein said salivary stimulant isselected from the group consisting of citric acid, tartaric acid, malicacid, fumaric acid, adipic acid, succinic acid, acid anhydrides thereof,acid salts thereof and combinations thereof.
 43. A drug formulation asclaimed in claim 36, wherein said salivary stimulant is an effervescentagent.
 44. A drug formulation as claimed in claim 43, wherein saideffervescent agent is the result of a reaction of a soluble acid sourceand an alkali metal carbonate or carbonate source.
 45. A drugformulation as claimed in claim 2, wherein the formulation is capable ofdissolving or dispersing in a patient's mouth within 1 minute afteradministration without the co-administration of a fluid.
 46. A drugformulation as claimed in claim 1, arranged for direct un-encapsulatedadministration to the oral cavity.
 47. A drug formulation as claimed inclaim 1, wherein the particles are non-compressed.
 48. A method ofpreparing a drug formulation as claimed in claim 1, comprising formingthe particles by melt-coating core particles with a coating materialthat includes a quantity of the water-soluble excipient and, optionally,a quantity of the binder, at a temperature below the melting point ordecomposition temperature of the active agent.
 49. Use of a drugformulation as claimed in claim 1, or a drug formulation is prepared bya method as claimed in claim 48, for the preparation of a medicament fortreating a human or animal patient, wherein the formulation isadministered directly and in an un-encapsulated form to the patient'soral cavity.
 50. A method of treating a human or animal patient, whereina formulation as claimed in claim 1, is administered in aun-encapsulated form directly into the patient's oral cavity.
 51. A drugdelivery system comprising a dosing device comprising a housing and anactuator, said device containing at least one unit dose of a drugformulation as claimed in claim 1, said device upon actuation deliveringa unit dose of said drug formulation such that an effective dose of saiddrug cannot be delivered into the lower lung of a human patient.
 52. Thedrug delivery system of claim 51 wherein said at least one unit dose iscontained in a reservoir.
 53. The drug delivery system of claim 51further comprising a metering component to meter a unit dose from saidreservoir upon actuation of said system.
 54. The drug delivery system ofclaim 51 comprising multiple unit doses, wherein said unit doses areindividually metered prior to said actuation.
 55. The drug deliverysystem of claim 51 further comprising sachets, each sachet containingsaid individually metered unit dose.
 56. The drug delivery system ofclaim 55 wherein said sachets are aligned linearly in the form of astrip.
 57. The drug delivery system of claim 56 wherein said strip is inthe form of a roll.
 58. The drug delivery system of claim 57 furthercomprising blisters on a substrate base, each blister containing saidindividually metered unit dose, said blisters covered by a seal.
 59. Thesystem of claim 58 wherein said blisters are aligned linearly in theform of a strip.
 60. The system of claim 59 wherein said strip is in theform of a roll.
 61. A method of treating a patient with an active agentfor gastrointestinal deposition comprising administering a formulationcomprising a non-compressed free flowing plurality of particlescomprising an active agent and a water-soluble excipient, said particleshaving a mean diameter of greater than 10 μm to about 1 mm, and saidformulation dissolving in a patient's mouth within 1 minute afteradministration without the co-administration of a fluid.
 62. A method oftreating a patient with an active agent for gastrointestinal depositioncomprising formulating a drug formulation comprising a non-compressedfree flowing plurality of particles comprising an active agent and awater-soluble excipient, said particles having a mean diameter ofgreater than 10 μm to about 1 mm, and said formulation dissolving in apatient's mouth within 1 minute after administration without theco-administration of a fluid, containing said drug formulation in a drugdelivery, said device upon actuation delivering a unit dose of said drugformulation such that an effective dose of said drug cannot be deliveredinto the lower lung of a human patient; and administering a unit dose ofsaid particles to the oral cavity.
 63. A method of preparing a drugdelivery system for gastrointestinal deposition of an active agentcomprising formulating a drug formulation comprising a non-compressedfree flowing plurality of particles comprising an active agent and awater-soluble excipient, said particles having a mean diameter ofgreater than 10 μm to about 1 mm, and said formulation dissolving in apatient's mouth within 1 minute after administration without thecoadministration of a fluid, containing said drug formulation in a drugdelivery, said device upon actuation delivering a unit dose of said drugformulation such that an effective dose of said drug cannot be deliveredinto the lower lung of a human patient.
 64. The system of claim 51wherein said active agent is an antibiotic.
 65. The system of claim 64wherein said antibiotic is a macrolide antibiotic.
 66. The system ofclaim 65 wherein said macrolide antibiotic is selected from the groupconsisting of erythromycin, dirithromycin, josamycin, midecamycin,kitasamycin, tylosin, roxithromycin, rokitamycin, oleandomycin,miocamycin, flurithromycin, rosaramicin, azithromycin, clarithromycin,and pharmaceutically acceptable salts thereof.
 67. The system of claim65 wherein said macrolide antibiotic is selected from the groupconsisting of erythromycin, clarithromycin, and pharmaceuticallyacceptable salts thereof
 68. A method of treating a patient with amacrolide antibiotic for gastrointestinal deposition comprisingadministering a drug formulation for gastrointestinal depositioncomprising a non-compressed free flowing plurality of particlescomprising a macrolide antibiotic and a water-soluble excipient, saidparticles having a mean diameter of greater than 10 μm to about 1 mm,said formulation dissolving in a patient's mouth within 1 minute afteradministration without the coadministration of a fluid.
 69. The methodof claim 68 wherein said formulation dissolves in a patient's mouthwithin 30, or 15 seconds after administration without thecoadministration of a fluid.
 70. The method of claim 68 wherein saidparticles comprise at least about 50%, 60% or 75% drug.
 71. A macrolideantibiotic formulation for gastrointestinal deposition comprising anon-compressed free flowing plurality of particles comprising amacrolide antibiotic and a water-soluble excipient, said particleshaving a mean diameter of greater than 10 μm to about 1 mm, saidformulation dissolving in a patient's mouth within 1 minute afteradministration without the coadministration of a fluid.
 72. Aformulation for gastrointestinal deposition comprising a non-compressedfree flowing plurality of particles comprising an active agent and awater-soluble excipient, said particles having a mean diameter ofgreater than 10 μm to about 1 mm, said formulation dissolving in apatient's mouth within 1 minute after administration without theco-administration of a fluid, said particles comprising less than 5%hydrophobic material.
 73. The formulation of claim 72 wherein saidparticles are prepared by a process comprising melt granulating saidwater soluble excipient and the active agent to form a homogenousmixture.
 74. The formulation of claim 72 wherein said particles areprepared by a process comprising melt coating said water solubleexcipient onto said active agent.
 75. The formulation of claim 73 whichis prepared without the use of an aqueous fluid.
 76. A drug formulationas claimed in claim 1, wherein the water-soluble excipient is xylitol77. A drug formulation as claimed in claim 1, wherein the active agentis paracetamol.
 78. A drug formulation as claimed in claim 1, beingadapted to provide both immediate release and controlled release of theactive agent.
 79. A drug formulation as claimed in claim 78, comprisinga free flowing plurality of particles comprising an active agent and awater-soluble excipient, wherein at least a portion of the particlescomprise active agent and at least one delayed release excipient.
 80. Adrug formulation as claimed in claim 78, wherein a first portion of theparticles comprises at least one delayed release excipient, to providecontrolled release of active agent, and a second portion of theparticles does not include any delayed release excipients, to provideimmediate release of active agent.
 81. A method of treating a human oranimal patient, wherein a formulation as claimed in claim 2, isadministered in a un-encapsulated form directly into the patient's oralcavity.
 82. A drug delivery system comprising a dosing device comprisinga housing and an actuator, said device containing at least one unit doseof a drug formulation as claimed in claim 2, said device upon actuationdelivering a unit dose of said drug formulation such that an effectivedose of said drug cannot be delivered into the lower lung of a humanpatient.
 83. A method of treating a human or animal patient, wherein aformulation prepared by a method as claimed in claim 48, is administeredin a un-encapsulated form directly into the patient's oral cavity.
 84. Adrug delivery system comprising a dosing device comprising a housing andan actuator, said device containing at least one unit dose of a drugformulation that was prepared by a method as claimed in claim 48, saiddevice upon actuation delivering a unit dose of said drug formulationsuch that an effective dose of said drug cannot be delivered into thelower lung of a human patient.